This is a submission of a competitive renewal application, MH 45074: "Clozapine Treatment of Schizophrenic Outpatients". Over the last ten years, the new generation antipsychotics clozapine, risperidone, olanzapine, quetiapine, and ziprasidone have been approved and introduced for the treatment of schizophrenia. Of these agents, only clozapine has been shown to have superior efficacy to conventional antipsychotics, and is FDA approved for treatment-resistant patients with schizophrenia. However, up to 50 percent of patients adequately treated with clozapine will fail to respond, and will continue to exhibit clinically significant residual positive and negative symptoms and cognitive impairments. These patients represent a major therapeutic challenge and raise the question: What treatment options are available for these patients? The major emerging treatment trend is to use a second antipsychotic medication. This clinical practice has become relatively widespread, but there is little empirical evidence to support the validity of this approach. We will conduct a 16-week randomized, parallel group, double-blind comparison of adjunctive risperidone and placebo in clozapine-treated patients with schizophrenia to address two primary aims: is adjunctive risperidone superior to placebo for the treatment of persistent positive symptoms and cognitive impairments in clozapine-treated patients with schizophrenia, and three secondary aims: is adjunctive risperidone superior to placebo for the treatment of persistent negative symptoms and functional impairments, and is adjunctive risperidone associated with increased incidence of side effects as compared to placebo in clozapine-treated patients with schizophrenia. We will perform biweekly positive and negative symptom and side effect assessments, and baseline and end of study neuropsychological and functional assessments. The study will provide new information on the clinical utility of adjunctive risperidone in treatment-resistant patients who fail to adequately respond to clozapine.